The primary purpose of this randomized trial is to test the effectiveness of a comprehensive, universal prevention program (HealthWise: Learning Life Skills for Young Adults) to reduce the risk of HIV/AIDS and STDs, as well as substance use, among adolescents in South Africa. This program, which integrates a two-year school-based curriculum with other school and community resources, will be implemented with three cohorts of youth aged 14 to16. Schools will be assigned to either intervention or comparison conditions. Specifically, the aims of this study are to: (a) Evaluate the effectiveness of the HealthWise program in preventing drug use and sexual risk-taking behaviors (and the co- occurrence of these), to delay the onset of sexual activity among virgins, to increase condom use, and to increase positive use of leisure time; (b) Identify which programmatic elements of HealthWise are theoretically and practically more effective in understanding and changing risk behavior in the South African cultural context; (c) Disentangle the theoretical interplay of comorbid risk and protective factors, in particular from a developmental systems perspective; (d) Test a unique methodology that times data collection with the timing of expected outcomes, and; (e) Evaluate the sustainability of the program. Although based on a U.S. model, HealthWise is specifically adapted to the cultural context in which it is given and has been a joint effort among U.S. and South African collaborators. Unique aspects of HealthWise include its focus on co-morbid risk behaviors, the leisure context, and getting youth to connect to the community. A longitudinal temporal design, using three sequential 8th-grade cohorts (2004, 2005, and 2006) will be employed. This innovative strategy, recommended by Collins and Graham (2002), will provide for four points of data collection during the 8th and 9th grades, spaced approximately six months apart, for each cohort. This strategy allows for more precise modeling of the processes under investigation. An extensive process evaluation protocol will be followed, as well. This study addresses a pressing need in South Africa as the separate, and interrelated, rates of substance use and risky sexual behavior is among the highest in the world (Flisher, 1993, 1996, in press).